Caroline J. Shaw

Pathophysiological mechanisms of high-intensity focused ultrasound-mediated vascular occlusion and relevance to non-invasive fetal surgery

High-intensity focused ultrasound (HIFU) is a non-invasive technology, which can be used occlude blood vessels in the body. Both the theory underlying and practical process of blood vessel occlusion are still under development and relatively sparse in vivo experimental and therapeutic data exist. HIFU would however provide an alternative to surgery, particularly in circumstances where serious complications inherent to surgery outweigh the potential benefits. Accordingly, the HIFU technique would be of particular utility for fetal and placental interventions, where open or endoscopic surgery is fraught with difficulty and likelihood of complications including premature delivery. This assumes that HIFU could be shown to safely and effectively occlude blood vessels in utero. To understand these mechanisms more fully, we present a review of relevant cross-specialty literature on the topic of vascular HIFU and suggest an integrative mechanism taking into account clinical, physical and engineering considerations through which HIFU may produce vascular occlusion. This model may aid in the design of HIFU protocols to further develop this area, and might be adapted to provide a non-invasive therapy for conditions in fetal medicine where vascular occlusion is beneficial.

Fetal movements as a predictor of health.

The key determinant to a fetus maintaining its health is through adequate perfusion and oxygen transfer mediated by the functioning placenta. When this equilibrium is distorted, a number of physiological changes, including reduced fetal growth, occur to favor survival. Technologies have been developed to monitor these changes with a view to prolong intrauterine maturity while reducing the risks of stillbirth. Many of these strategies involve complex interpretation, for example Doppler ultrasound for fetal blood flow and computerized analysis of fetal heart rate changes. However, even with these modalities of fetal assessment to determine the optimal timing of delivery, fetal movements remain integral to clinical decision‐making. In high‐risk cohorts with fetal growth restriction, the manifestation of a reduction in perceived movements may warrant an expedited delivery. Despite this, there has been little evolution in the development of technologies to objectively evaluate fetal movement behavior for clinical application. This review explores the available literature on the value of fetal movement analysis as a method of assessing fetal wellbeing, and demonstrates how interdisciplinary developments in this area may aid in the improvement of clinical outcomes.

Noninvasive high-intensity focused ultrasound treatment of twin-twin transfusion syndrome: A preliminary in vivo study

High-intensity focused ultrasound can ablate blood flow in the sheep placenta and may be translatable to human twin-twin transfusion syndrome. Splitting the babies Twin-twin transfusion syndrome is a complication of some twin pregnancies, where abnormal connections between the twins’ placental blood vessels result in unequal sharing of blood flow, with potentially lethal consequences. Although it is possible to separate the twins’ vasculature using fetoscopic laser occlusion of the connecting blood vessels, it is an invasive treatment with a high risk of complications. Shaw et al. used a sheep model of pregnancy to demonstrate the feasibility and relative safety of using high-intensity focused ultrasound to ablate blood flow through individual placental vessels. The authors used only healthy pregnant sheep, and the procedure still required surgical intervention to reach the uterus, but this approach may eventually offer a safer treatment alternative for human patients. We investigated the efficacy, maternofetal responses, and safety of using high-intensity focused ultrasound (HIFU) for noninvasive occlusion of placental vasculature compared to sham treatment in anesthetized pregnant sheep. This technique for noninvasive occlusion of placental vasculature may be translatable to the treatment of conditions arising from abnormal placental vasculature, such as twin-twin transfusion syndrome (TTTS). Eleven pregnant sheep were instrumented with maternal and fetal arterial catheters and time-transit flow probes to monitor cardiovascular, acid-base, and metabolic status, and then exposed to HIFU (n = 5) or sham (n = 6) ablation of placental vasculature through the exposed uterine surface. Placental vascular flow was occluded in 28 of 30 targets, and histological examination confirmed occlusion in 24 of 30 targets. In both HIFU and sham exposures, uterine contact reduced maternal uterine artery flow, but delivery of oxygen and glucose to the fetal brain remained normal. HIFU can consistently occlude in vivo placental vessels and ablate blood flow in a pregnant sheep model. Cardiovascular and metabolic fetal responses suggest that the technique is safe in the short term and potentially translatable to human pregnancy.

Altered autonomic control of heart rate variability in the chronically hypoxic fetus

Fetal heart rate variability (FHRV) has long been recognised as a powerful predictor of fetal wellbeing, and a decrease in FHRV is associated with fetal compromise. However, the mechanisms by which FHRV is reduced in the chronically hypoxic fetus have yet to be established. The sympathetic and parasympathetic influences on heart rate mature at different rates throughout fetal life, and can be assessed by time domain and power spectral analysis of FHRV. In this study of chronically instrumented fetal sheep in late gestation, we analysed FHRV daily over a 16 day period towards term, and compared changes between fetuses of control and chronically hypoxic pregnancy. We show that FHRV in sheep is reduced by chronic hypoxia, predominantly due to dysregulation of the sympathetic control of the fetal heart rate. This presents a potential mechanism by which a reduction in indices of FHRV predicts fetuses at increased risk of neonatal morbidity and mortality in humans. Reduction in overall FHRV may therefore provide a biomarker that autonomic dysregulation of fetal heart rate control has taken place in a fetus where uteroplacental dysfunction is suspected.

Trans-abdominal in vivo placental vessel occlusion using High Intensity Focused Ultrasound

Pre-clinically, High Intensity Focused Ultrasound (HIFU) has been shown to safely and effectively occlude placental blood vessels in the acute setting, when applied through the uterus. However, further development of the technique to overcome the technical challenges of targeting and occluding blood vessels through intact skin remains essential to translation into human studies. So too does the assessment of fetal wellbeing following this procedure, and demonstration of the persistence of vascular occlusion. At 115 ± 10 d gestational age (term~147 days) 12 pregnant sheep were exposed to HIFU (n = 6), or to a sham (n = 6) therapy through intact abdominal skin (1.66 MHz, 5 s duration, in situ ISPTA 1.3–4.4 kW.cm−2). Treatment success was defined as undetectable colour Doppler signal in the target placental vessel following HIFU exposures. Pregnancies were monitored for 21 days using diagnostic ultrasound from one day before HIFU exposure until term, when post-mortem examination was performed. Placental vessels were examined histologically for evidence of persistent vascular occlusion. HIFU occluded 31/34 (91%) of placental vessels targeted, with persistent vascular occlusion evident on histological examination 20 days after treatment. The mean diameter of occluded vessels was 1.4 mm (range 0.3–3.3 mm). All pregnancies survived until post mortem without evidence of significant maternal or fetal iatrogenic harm, preterm labour, maternal or fetal haemorrhage or infection. Three of six ewes exposed to HIFU experienced abdominal skin burns, which healed without intervention within 21 days. Mean fetal weight, fetal growth velocity and other measures of fetal biometry were not affected by exposure to HIFU. Fetal Doppler studies indicated a transient increase in the umbilical artery pulsatility index (PI) and a decrease in middle cerebral artery PI as a result of general anaesthesia, which was not different between sham and treatment groups. We report the first successful application of fully non-invasive HIFU for occlusion of placental blood flow in a pregnant sheep model, with a low risk of significant complications. This proof of concept study demonstrates the potential of this technique for clinical translation.

Uterine and fetal placental Doppler indices are associated with maternal cardiovascular function

BACKGROUND: The mechanism underlying fetal‐placental Doppler index changes in preeclampsia and/or fetal growth restriction are unknown, although both are associated with maternal cardiovascular dysfunction. OBJECTIVE: We sought to investigate whether there was a relationship between maternal cardiac output and vascular resistance and fetoplacental Doppler findings in healthy and complicated pregnancy. STUDY DESIGN: Women with healthy pregnancies (n=62), preeclamptic pregnancies (n=13), preeclamptic pregnancies with fetal growth restriction (n=15), or fetal growth restricted pregnancies (n=17) from 24–40 weeks gestation were included. All of them underwent measurement of cardiac output with the use of an inert gas rebreathing technique and derivation of peripheral vascular resistance. Uterine and fetal Doppler indices were recorded; the latter were z scored to account for gestation. Associations were determined by polynomial regression analyses. RESULTS: Mean uterine artery pulsatility index was higher in fetal growth restriction (1.37; P=.026) and preeclampsia+fetal growth restriction (1.63; P=.001) but not preeclampsia (0.92; P=1) compared with control subjects (0.8). There was a negative relationship between uterine pulsatility index and cardiac output (r2=0.101; P=.025) and umbilical pulsatility index z score and cardiac output (r2=0.078; P=.0015), and there were positive associations between uterine pulsatility index and peripheral vascular resistance (r2=0.150; P=.003) and umbilical pulsatility index z score and peripheral vascular resistance (r2= 0.145; P=.001). There was no significant relationship between cardiac output and peripheral vascular resistance with cerebral Doppler indices. CONCLUSION: Uterine artery Doppler change is abnormally elevated in fetal growth restriction with and without preeclampsia, but not in preeclampsia, which may explain the limited sensitivity of uterine artery Doppler changes for all these complications when considered in aggregate. Furthermore, impedance within fetoplacental arterial vessels is at least, in part, associated with maternal cardiovascular function. This relationship may have important implications for fetal surveillance and would inform therapeutic options in those pathologic pregnancy conditions currently, and perhaps erroneously, attributed purely to placental maldevelopment. Uterine and fetal placental Doppler indices are associated significantly with maternal cardiovascular function. The classic description of uterine and fetal Doppler changes being initiated by placental maldevelopment is a less plausible explanation for the pathogenesis of the conditions than that relating to maternal cardiovascular changes.

The role of cavitation in vascular occlusion

Ed Carstensen’s papers on the effects of ultrasound on plants were amongst the first that attracted me to study ultrasound bio-effects. It was little surprise to me that, when I first started looking at HIFU, his name was on many of the seminal papers in this area. And now, his papers on cavitation and vasculature inform our current research. Ed’s influence on bio-effects research stretches far beyond the borders of the USA Vascular occlusion has the potential to treat life-threatening conditions including twin-twin transfusion syndrome (occurring in fetuses that share a placenta). Sheep placental vessels have been used to develop HIFU treatment guidance, delivery (1.66MHz) and monitoring. Ultrasound imaging guidance/flow monitoring, with simultaneous acoustic cavitation detection in 82 targets in 14 pregnant sheep resulted in flow occlusion in 90%. Adverse events included skin erythema (18/82) and burns (10/82), but all resolved over 21 days. Analysis of acoustic cavitation required low pass (software) f...